Sachiko Miyagawa

A randomized double-blind trial of intravenous immunoglobulin for pemphigus

BACKGROUND Pemphigus is a rare life-threatening intractable autoimmune blistering disease caused by IgG autoantibodies to desmogleins. It has been difficult to conduct a double-blind clinical study for pemphigus partly because, in a placebo group, appropriate treatment often must be provided when the disease flares. OBJECTIVE A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of a single cycle of high-dose intravenous immunoglobulin (400, 200, or 0 mg/kg/d) administered over 5 consecutive days in patients relatively resistant to systemic steroids. METHODS We evaluated efficacy with time to escape from the protocol as a novel primary end point, and pemphigus activity score, antidesmoglein enzyme-linked immunosorbent assay scores, and safety as secondary end points. RESULTS We enrolled 61 patients with pemphigus vulgaris or pemphigus foliaceus who did not respond to prednisolone (> or =20 mg/d). Time to escape from the protocol was significantly prolonged in the 400-mg group compared with the placebo group (P < .001), and a dose-response relationship among the 3 treatment groups was observed (P < .001). Disease activity and enzyme-linked immunosorbent assay scores were significantly lower in the 400-mg group than in the other groups (P < .05 on day 43, P < .01 on day 85). There was no significant difference in the safety end point among the 3 treatment groups. LIMITATION Prednisolone at 20 mg/d or more may not be high enough to define steroid resistance. CONCLUSION Intravenous immunoglobulin (400 mg/kg/d for 5 d) in a single cycle is an effective and safe treatment for patients with pemphigus who are relatively resistant to systemic steroids. Time to escape from the protocol is a useful indicator for evaluation in randomized, placebo-controlled, double-blind studies of rare and serious diseases.

Late development of antidesmoglein 1 antibodies in pemphigus vulgaris: correlation with disease progression.

The coexistence of antidesmoglein 3 (Dsg3) and antidesmoglein 1 (Dsg1) autoantibodies is well described in patients with pemphigus vulgaris (PV); however, there is little evidence of sequential development of these two autoantibodies. Autoantibody responses to Dsg3 and Dsg1 were studied in seven PV patients over time by enzyme‐linked immunosorbent assay, using baculovirus expressed recombinant fusion proteins. All patients had anti‐Dsg3 IgG antibodies at presentation. Two patients developed anti‐Dsg1 later in the course of the disease. The transition in autoantibody profile was associated with disease progression to generalized PV involving mucous membranes and skin in both patients; one patient initially presented with a predominantly mucosal phenotype, the other with herpetiform pemphigus‐like features. These findings demonstrate that there is an extension of autoimmune response from anti‐Dsg3 only to both anti‐Dsg3 and anti‐Dsg1 in some patients, which is associated with an alteration in clinical expression in PV.

Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin

Skin eruptions with features of subacute cutaneous lupus erythematosus occurred in a patient with dermatomyositis who was taking griseofulvin. The patient had antibodies against SSA/Ro and SSB/La antigens. Skin rashes disappeared after discontinuation of griseofulvin and recurred on challenge with the drug. These findings support previous studies that the photoactive drug may be synergistic with anti-SSA/Ro antibody to produce lesions of subacute cutaneous lupus erythematosus.

Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects

OBJECTIVE To investigate HLA class II allele associations with autoantibody responses to Ro/SS-A and La/SS-B among Japanese subjects. METHODS Haplotype and allele distributions, along with molecular polymorphisms, of HLA class II genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 41 Japanese women with precipitating autoantibodies to Ro/SS-A and/or La/SS-B. RESULTS Among women with both Ro/SS-A and La/SS-B antibodies, the HLA class II haplotype DRB1*08032/DQA1*0103/DQB1*0601 and DRB1*08032 allele showed significantly increased frequencies compared with patients with anti-Ro/SS-A alone or with normal controls. All women with both anti-Ro/SS-A and anti-La/SS-B, but not those with anti-Ro/SS-A alone, carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the hypervariable regions of the DRB1 chain. All anti-Ro/SS-A positive women carried 1 or 2 alleles of DQB1*06 and DQB1*03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. HLA class II allele distributions did not differ among 3 anti-Ro/SS-A positive groups with different disease expressions, i.e., patients with systemic lupus erythematosus, patients with primary Sjögrens syndrome, and women with no apparent symptoms of rheumatic disease. CONCLUSION HLA class II allele distributions differ among anti-Ro/SS-A positive subjects according to the presence or absence of coexisting anti-La/SS-B antibodies, but not according to disease expression. Our findings suggest that different HLA class II molecules might control the development of anti-Ro/SS-A and/or anti-La/SS-B antibodies in the autoimmune response to the Ro/SS-A-La/SS-B complex.

Role for connexin 26 in metastasis of human malignant melanoma: communication between melanoma and endothelial cells via connexin 26.

Connexins form the intercellular channels of the gap junction and play an integral part in a variety of biological functions, such as maintaining tissue homeostasis, cell growth control, and development. Previously it was demonstrated that the expression of connexin 26 (Cx26) can increase the metastatic potential of mouse melanoma cells. The objective of the study was to investigate the role Cx26 plays in the metastasis of human melanoma cells, focusing on the communication between melanoma cells and endothelial cells.

Improvement of psoriasis during imatinib therapy in a patient with a metastatic gastrointestinal stromal tumour.

SIR, Interferon alfa (IFN-a) therapy is highly effective in patients with chronic myelogenous leukaemia and other malignant diseases. Most side-effects, such as chills, malaise, myalgia and fatigue, are transient and tend to disappear with ongoing therapy, while others, such as anorexia, neurological and mood disorders, are dose-related and need dose adjustment or withdrawal of IFN-a. Induction of immunemediated disease, including thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, thrombocytopenia, autoimmune haemolytic anaemia, and insulin-dependent diabetes mellitus, has also been described. Moreover, other immunological entities, such as myasthenia gravis, vitiligo, lichen planus, Henoch–Schönlein purpura and Sjögren syndrome, have been reported after IFN-a therapy for chronic viral hepatitis or multiple sclerosis (MS). Here, we report on the first case of systemic sclerosis (SSc) developing after therapy with IFN-a for chronic myelogenous leukaemia. In October 1998, a 52-year-old-woman without a personal or a familiar history of autoimmune disease, was diagnosed as having chronic myelogenous leukaemia, with a karyotype 46,XX,t(9;22), bcr ⁄ abl positive in all the metaphases. She was given hydroxyurea 20 mg kg day for 2 months and then IFN-a 2a to a maximum daily dose of 10 · 10 U. In June 1999, cytogenic evaluation showed a normalization of the karyotype in up to 33% of metaphases. Meanwhile, treatment was reduced to 6 · 10 U day for the appraisal of arthralgias, ataxia and depression. In June 2000 a further evaluation revealed the loss of efficacy of therapy (Ph chromosome positive in all the analysable metaphases). In the same period, the patient experienced fever, dyspnoea and oedema of the extremities. Laboratory findings were normal, except for an increased erythrocyte sedimentation rate (ESR, 50 mm in the first hour). Chest X-ray and computed tomography (CT) of the lung demonstrated the presence of pulmonary vascular congestion. Cardiac function, evaluated by electrocardiogram and Doppler echocardiography, was normal. The possible diagnosis of congestive heart failure was discarded and the patient’s symptoms were ascribed to a leak capillary syndrome secondary to interferon therapy; interferon therapy was interrupted. Peripheral oedema and respiratory symptoms improved on treatment with diuretics. Nevertheless, 3 months later, in November 2000 she experienced dyspnoea, oedema of both the upper and lower limbs and progressive skin thickening of the hands and wrists. A further echocardiographic evaluation revealed a normal ejection fraction (70%) and minimal tricuspid regurgitation with increased pulmonary artery pressure (34 mmHg). CT of the chest showed a picture of diffuse parenchymal and interstitial fibrosis with multiple areas of ground-glass attenuation. Pulmonary function tests demonstrated the presence of reduced volumes with an impaired diffusion capacity for carbon monoxide (DLCO, 46% predicted). Oesophagogastroduodenoscopy showed a total absence of peristalsis. Laboratory examination indicated: elevated ESR (80 mm in the first hour), impaired renal function (creatinine, 1Æ8 mg dL) with mild proteinuria (72 mg 24 h) and positive antisclero-70 antibodies. Her complete major histocompatibility phenotype was HLA-DRB1*11; 07, DQA*05;0201, DQB*03;02, A28, A24, B35, B13, Bw4, Bw6, Cw4. Capillaroscopy findings were consistent with scleroderma, showing multiple microhaemorrhages, dilation, distortion and rarefaction of capillaries. No skin biopsy was performed. A diagnosis of localized SSc was put forward, according to LeRoy et al. The patient was given loop diuretics, cyclophosphamide 100 mg day, prostanoids (iloprost, 2 ng kg min for 8 h for five consecutive days and then thrice monthly), steroids (methylprednisolone 750 mg intravenously for 3 days and then prednisone 25 mg day). In the following months the patient’s clinical condition improved, scleroedema decreased, the skin thickening partially receded and the signs of alveolitis were no longer detectable at a further CT evaluation of the lung (October 2001). Therapy has been gradually tapered and the patient is now receiving cyclophosphamide 50 mg day, prednisone 12Æ5 mg day, iloprost 2 ng kg min for 8 h every 3 weeks and hydroxyurea 10 mg kg on every alternate day. The patient’s main clinical and laboratory findings, before and after 10 months of therapy, are summarized in Table 1. Several authors showed that IFN-a therapy for malignancies, chronic viral hepatitis or MS may trigger the formation of autoantibodies directed toward various substrates, such as thyroid, platelets, erythrocytes, pancreas, parietal cells and nuclei. Their occurrence is sometimes, but not necessarily, coupled with the onset or the exacerbation of autoimmune diseases. In most cases endocrine disorders are described, but rheumatic and collagen–vascular diseases have been observed as well. Nevertheless, to date, no reports of SSc after interferon therapy have been made. However, Wandl et al. noticed that patients who develop antinuclear antibodies may experience Raynaud’s phenomenon, one of the diagnostic findings in SSc. Moreover, Black et al. pointed out that IFN-a therapy in the treatment of scleroderma may be deleterious, exacerbating life-threatening symptoms and precipitating the lung deterioration. As far as our patient is concerned, the laboratory findings, typical vascular alterations and ⁄ or clinical signs of autoimmunity are ascribable to interferon therapy. The patient had neither a personal nor a familiar history of autoimmunity, and a clear temporal relation between IFN-a administration and the occurrence of initial symptoms can be seen. Besides, she did receive IFN-a continuously for approximately 2 years. Fattovich et al. indeed noticed that de novo immuneBritish Journal of Dermatology 2002; 147: 385–410.

Lichen planus pemphigoides‐like lesions induced by cinnarizine

A 72‐year‐old woman developed a lichen planus pemphigoides‐like eruption following the administration of cinnarizine. The eruption recurred on challenge with the drug. Direct immunofluorescence studies of the lesions demonstrated deposition of IgG, IgM and C3 on colloid bodies and fibrin at the epidermal basement membrane zone. Circulating IgG antibasement membrane zone antibodies were detected at high titres, with no complement‐ fixing activities. To our knowledge, this is the first report of immunologically defined lichen planus pemphigoides induced by a drug.

Atypical pemphigus associated with monoclonal IgA gammopathy

We describe a 60-year-old woman with atypical pemphigus and IgA-lambda monoclonal gammopathy. Histopathologic study of vesiculopustular lesions showed intraepidermal acantholytic and neutrophilic blisters. Direct immunofluorescence revealed intercellular IgG deposition with concurrent deposits of IgA and C3. Indirect immunofluorescence and immunoblotting studies revealed that the patient had circulating IgG anti-intercellular antibodies that recognized the 150 kd desmoglein (pemphigus foliaceus antigen) in bovine desmosome preparation. Immunoblot studies with human epidermal extract showed that the IgG of this patient exclusively reacted with the 140 kd protein (between the 150 kd human desmoglein and the 130 kd human pemphigus vulgaris antigen), the nature of which is currently unknown. The patient also had IgA anti-intercellular autoantibodies, which reacted with the desmoglein in the bovine desmosome sample but did not show any reactivity in human epidermal extract.

Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid.

Bullous pemphigoid (BP), an autoimmune skin disease of the elderly, is mediated by autoantibodies that bind to hemidesmosomes of epidermal basal cells. This study investigated BP‐associated HLA‐DR and ‐DQ genes among Japanese patients. We analyzed HLA‐DR and ‐DQ genes among 23 Japanese BP patients based on the polymerase chain reaction‐restriction fragment length polymorphism. Eighteen of these 23 patients (78%) carried at least one allele of HLA‐DRB1*04 or DRB1*1101, with significant increases in HLA‐DRB1*04 (*0403, *0406)/DQA1*0301/DQB1*0302 and DRB1*1101/DQA1*0505/DQB1*0302 haplotypes as well as the individual alleles DRB1*1101 and DQB1*0302 (corrected p<0.05 for each comparison), when compared to control subjects. These data differ from the accepted DQB1*0301 (DQ7) association with the same disease among Caucasians. These findings indicate that different HLA class II haplotypes genetically influence susceptibility to BP among different ethnic groups. Our findings, together with previous reports on Caucasian patients with the pemphigoid group of bullous diseases, suggest that HLA‐DRB1 molecules might participate in the regulation of autoimmune responses to BP antigens.

Relationship among human herpesvirus 6 reactivation, serum interleukin 10 levels, and rash/graft-versus-host disease after allogeneic stem cell transplantation

BACKGROUND The relationship between herpesvirus reactivation and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) is unclear. OBJECTIVE We sought to examine the relationship between human herpesvirus (HHV) reactivation and rash/GVHD after allo-SCT by prospective evaluation. METHODS Fifteen patients who had received allo-SCT underwent prospective serial examinations for human herpesvirus 6 (HHV-6), HHV-7, cytomegalovirus, and Epstein-Barr virus DNA in the blood by polymerase chain reaction and real-time polymerase chain reaction. Serum interferon gamma, interleukins 4 and 10, tumor necrosis factor alpha, and soluble interleukin 2 receptor (sIL-2R) were also measured. RESULTS In 10 of 15 patients, macular/papular eruptions were seen after allo-SCT and GVHD was diagnosed. In 8 patients with rash, HHV-6 DNA levels correlated with the cutaneous manifestation. Interleukin 10 and sIL-2R also increased in association with rash. LIMITATIONS The number of patients in our study was relatively small. Not all patients were examined for cytokines and sIL-2R. CONCLUSIONS HHV-6 reactivation may be involved in the pathogenesis of rash/GVHD after allo-SCT.